Guanfacine is a central alpha2A-adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as a monotherapy and as an adjunctive therapy to stimulant medications. Guanfacine hydrochloride, a pharmaceutically acceptable salt of guanfacine, is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in acetone. The chemical designation for guanfacine hydrochloride is N-amidino-2-(2,6-dichlorophenyl)-acetamide monohydrochloride. The chemical structure is:

Guanfacine and its pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 3,632,645. U.S. Pat. No. 5,854,290 discloses the method of treating a behavioral disinhibition (e.g. Attention-Deficit Hyperactivity Disorder) in a primate with minimal sedative side effects by administering thereto a therapeutically effective amount of guanfacine.
U.S. Pat. No.'s. 6,287,599 and 6,811,794 describe sustained release tablet compositions of guanfacine, comprising at least one non-pH dependent sustained release agent, and at least one pH dependent agent that increases the rate of release of guanfacine from the tablet at a pH in excess of 5.5.
Guanfacine is presently marketed only in solid dosage forms i.e. immediate release and extended release tablets for oral administration. However, these solid dosage forms are not suited for patients who have difficulty in swallowing. Further, solid dosage forms may not be convenient, when chronic therapy is needed.
Therefore, there exists a need in the art for liquid compositions of guanfacine for better patient compliance, convenience and dose flexibility. Of particular advantage would be extended release liquid compositions that can provide effective plasma levels over a prolonged period of time. In view of this, extended release liquid compositions are clearly advantageous over the presently available solid dosage forms.
However, it remains a great challenge to formulate an extended release liquid composition of guanfacine. First challenge is to avoid the release of guanfacine from extended release units into a liquid carrier during storage, and to release only when the composition enters the gastrointestinal tract. Guanfacine may leach out from the extended release units into the liquid carrier during storage, thus obliterating the whole objective of the extended release. Furthermore, the irregular release may lead to sub-therapeutic or toxic effects leading to serious medical conditions. Another challenge with the liquid composition of guanfacine is the stability of guanfacine, both during the manufacturing process and shelf-life.
The inventors of the present invention have addressed all these challenges and have for the first time developed extended release liquid compositions of guanfacine. The compositions described herein are capable of providing consistent in-vitro extended release of guanfacine which further ensures steady plasma concentrations throughout the shelf life of the compositions. Further, said extended release liquid compositions provide desired in-vivo release of guanfacine and are bioequivalent to a reference composition. Furthermore, the extended release liquid compositions are stable both during manufacturing and storage period.
Therefore, the present invention is a significant advance over the available solid dosage forms of guanfacine and fulfills the long felt need to improve patient compliance by providing an extended release liquid composition of guanfacine with consistent release and acceptable stability.
The extended release liquid compositions of guanfacine offer additional advantages as they are easy to manufacture with functional reproducibility. The extended release liquid compositions described herein are provided with a pleasant mouth feel thereby further enhancing patient compliance and ease of administration.